Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway

Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.

血液营养指标预测老年粗隆间骨折术后1年的死亡率

目的回顾性分析血液营养指标对预测老年粗隆间骨折患者术后1年死亡率的价值。方法选取2012年1月-2016年1月99例年龄>65岁,采用髓内钉手术治疗的粗隆间骨折患者。分析患者的性别、年龄、入院血清白蛋白、总蛋白、球蛋白、前白蛋白、淋巴细胞计数(TLC)、血红蛋白、血清钾及钙等因素。手术后随访1年,随访患者生存情况。结果 99例患者,术后随访1年内死亡35例。性别比较无差异(P>0.05);男女患者血液参数和淋巴细胞计数比较,差异无统计学意义(P>0.05);男女的年龄、白蛋白含量及血红蛋白含量比较,差异有统计学意义(P<0.05)。多因素线性回归分析显示,年龄和血红蛋白含量是预测术后1年死亡率的影响因素。结论营养指标对粗隆间骨折患者的术后1年死亡率有预测价值,年龄、血红蛋白及白蛋白对死亡率有影响。

New blood markers detection technology:A leap in thediagnosis of gastric cancer

Gastric cancer(GC) is still one of the malignant tumors with high morbidity and mortality in the world, with a 5-year survival rate of less than 30%. GC is often either asymptomatic or causes only nonspecific symptoms in its early stages, whereas when the symptoms manifest, the cancer has usually reached an advanced stage, which is one of the main causes of its relatively poor prognosis. Hence, the main focus of GC research has been on discovering new tools and technology to predict, screen and diagnose g C at an early stage which would prompt early treatment. With the tremendous advances in the OMICS technology, serum proteomics has been in the limelight of cancer research over the last few decades and has steered the development of several methods helping to understand the mechanisms underlying gastric carcinogenesis, resulting in the identification of a large number of molecular targets such as circulating tumor cells(CTCs), cell free DNA(cf DNA) and cell tumor DNA(ct DNA) and their sub-molecular components such as mi RNA, that show great promise as GC biomarkers. In this review, we are underlying the recent breakthroughs about new blood markers technology for GC while scrutinizing the potential clinical use of CTCs, cf DNA, ct DNA and the role of the methylation of their submolecular components in the pathogenesis, diagnosis and management of GC.

Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell

Gastric cancer(GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell(TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC(GATIC), substantial studies have been performed to(1) identify the putative specific cell markers for purification and functional validation of GATICs;(2) trace the origin of GATICs; and(3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors(TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.

Microstructure, mechanical and corrosion properties of magnesium alloy bone plate treated by high-energy shot peening

To enhance the mechanical properties and corrosion resistance of magnesium alloys,high-energy shot peening(HESP)was used.According to the results,the in-situ surface nanocrystallization(ISNC)microstructure was fabricated on the magnesium alloy surface,and its formation mechanism was the coordination among twins,dislocations,subgrain boundary formation and dynamic recrystallization.Under the released surface stress of sample,the residual compressive stress and microhardness rose,thus enhancing compactness of the surface passivation film Mg(OH)2.Besides,the corrosion rate dropped by 29.2% in maximum.In the polarization curve,the maximum positive shift of the corrosion potential of sample was 203 mV, and the corrosion current density decreased by 31.25% in maximum.Moreover,the compression resistance and bending resistance of the bone plate were enhanced,and the maximum improvement rates were 18.2% and 23.1%,respectively.Accordingly,HESP significantly enhanced mechanical properties and corrosion resistance of magnesium alloys.

Expert consensus of Chinese Association for the Study of Pain on the application of ozone therapy in pain medicine

This consensus was compiled by first-line clinical experts in the field of pain medicine and was organized by the Chinese Association for the Study of Pain.To reach this consensus,we consulted a wide range of opinions and conducted indepth discussions on the mechanism,indications,contraindications,operational specifications and adverse reactions of ozone iatrotechnique in the treatment of pain disorders.We also referred to related previous preclinical and clinical studies published in recent years worldwide.The purpose of this consensus is to standardize the rational application of ozone iatrotechnique in pain treatment,to improve its efficacy and safety and to reduce and prevent adverse reactions and complications in this process.

Quantitative analysis of a novel antimicrobial peptide in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry

We described the first results of a quantitative ultra performance liquid chromatographytandem mass spectrometry method for a novel antimicrobial peptide （phylloseptin, PSN-1）. Chromatographic separation was accomplished on a Waters bridged ethyl hybrid （BEH） C18 （50mm× 2.1 mm, 1.7 μm） column with acetonitrile-water （25：75, v/v） as isocratic mobile phase. Mass spectrometry detection was performed in the positive electrospray ionization mode and by monitoring of the transitions at m/z 679.6/120, 509.6/120 （PSN-1） and m/z 340.7/165 （Thymopentin, IS）. Protein precipitation was investigated and the recovery was satisfactory （above 82%）. The method was shown to be reproducible and reliable with intra-day precision below 5.3%, inter-day precision below 14.2%, and linear range from 0.02 to 2 lag/mL with r〉0.994. The method was successfully applied to a pharmacokinetic study of PSN-1 in rats after intravenous administration.

卵圆孔的解剖学研究及其临床意义

目的观察卵圆孔(FO)的形态及变异,为三叉神经痛、海绵窦区肿瘤的诊治提供参考依据。方法选取83例结构完整的颅骨标本,采用游标卡尺测量卵圆孔长度、宽度。分别测量FO与同侧颞骨岩尖(APP)、后床突(PCP)之间的距离,分别记为FO-APP,FO-PCP;记录FO形态特点。结果①FO具有如下形态:椭圆形98例;“D”字型60例;三角形3例;圆形2例;不规则形2例;缝1例。FO内具有骨棘3例,骨结节3例,骨刺2例。②左侧FO长度、宽度分别为(7.37±1.21)和(4.28±0.99)mm;FO与颞骨岩尖、后床突距离分别为(9.88±3.54)和(15.68±3.49)mm;右侧FO长度、宽度分别为(7.84±1.18)和(4.06±0.99)mm;FO与颞骨岩尖、后床突距离分别为(9.44±3.20)和(16.74±4.57)mm。③右侧FO长度高于左侧(P<0.05);左侧FO宽度与FO-APP呈负相关(r=-0.526,P=0.043);右侧FO宽度与FO-APP呈负相关(r=-0.341,P=0.039);右侧FO宽度与FO-PCP呈负相关(r=-0.369,P=0.047)。结论分析FO与颞骨岩尖、后床突等重要结构解剖学参数不仅提高脑外科医生对颅中窝解剖特征的认识,而且对三叉神经减压、海绵窦肿瘤的诊疗具有重要意义。

Factors influencing oil recovery by surfactant-polymer flooding in conglomerate reservoirs and its quantitative calculation method

This study aims to clarify the factors influencing oil recovery of surfactant-polymer(SP)flooding and to establish a quantitative calculation model of oil recovery during different displacement stages from water flooding to SP flooding.The conglomerate reservoir of the Badaowan Formation in the seventh block of the Karamay Oilfield is selected as the research object to reveal the start-up mechanism of residual oil and determine the controlling factors of oil recovery through SP flooding experiments of natural cores and microetching models.The experimental results are used to identify four types of residual oil after water flooding in this conglomerate reservoir with a complex pore structure:oil droplets retained in pore throats by capillary forces,oil cluster trapped at the junction of pores and throats,oil film on the rock surface,isolated oil in dead-ends of flow channel.For the four types of residual oil identified,the SP solution can enhance oil recovery by enlarging the sweep volume and improving the oil displacement efficiency.First,the viscosity-increasing effect of the polymer can effectively reduce the permeability of the displacement liquid phase,change the oil-water mobility ratio,and increase the water absorption.Furthermore,the stronger the shear drag force of the SP solution,the more the crude oil in a porous medium is displaced.Second,the surfactant can change the rock wettability and reduce the absorption capacity of residual oil by lowering interfacial tension.At the same time,the emulsification further increases the viscosity of the SP solution,and the residual oil is recovered effectively under the combined effect of the above two factors.For the four start-up mechanisms of residual oil identified after water flooding,enlarging the sweep volume and improving the oil displacement efficiency are interdependent,but their contribution to enhanced oil recovery are different.The SP flooding system primarily enlarges the sweep volume by increasing viscosity of solution to start two kinds of residual oil such as oil droplet retained in pore throats and isolated oil in dead-ends of flow channel,and primarily improves the oil displacement efficiency by lowing interfacial tension of oil phase to start two kinds of residual oil such as oil cluster trapped at the junction of pores and oil film on the rock surface.On this basis,the experimental results of the oil displacement from seven natural cores show that the pore structure of the reservoir is the main factor influencing water flooding recovery,while the physical properties and original oil saturation have relatively little influence.The main factor influencing SP flooding recovery is the physical and chemical properties of the solution itself,which primarily control the interfacial tension and solution viscosity in the reservoir.The residual oil saturation after water flooding is the material basis of SP flooding,and it is the second-most dominant factor controlling oil recovery.Combined with the analysis results of the influencing factors and reservoir parameters,the water flooding recovery index and SP flooding recovery index are defined to further establish quantitative calculation models of oil recovery under different displacement modes.The average relative errors of the two models are 4.4%and 2.5%,respectively;thus,they can accurately predict the oil recovery of different displacement stages and the ultimate reservoir oil recovery.

Medical ozone alleviates acute lung injury by enhancing phagocytosis targeting NETs via AMPK/SR-A1 axis

Acute lung injury(ALI)linked to sepsis has a high mortality rate,with limited treatment options available.In recent studies,medical ozone has shown the potential to alleviate inflammation and infection.Here,we aimed to evaluate therapeutic potential of medical ozone in a mouse model of the sepsis-induced ALI by measuring behavioral assessments,lung function,and blood flow.Protein levels were quantified by Western blotting.In vitro,we performed experiments on bone marrow-derived macrophages(BMDMs)to investigate the effect of adenosine monophosphate(AMP)-activated protein kinase(AMPK)inhibitors and agonists on their phagocytic activity.The results showed that medical ozone significantly improved the survival rate,ameliorated lung injury,and enhanced lung function and limb microcirculation in mice with ALI.Notably,medical ozone inhibited the formation of neutrophil extracellular traps(NETs),a crucial factor in the ALI development.Additionally,medical ozone counteracted the elevated levels of tissue factor,matrix metalloproteinase-9,and interleukin-1β.In the ALI mice,the effects of ozone were abolished,and BMDMs showed an impaired capacity to engulf NETs following the Sr-a1 knockout.Under normal physiological conditions,the administration of an AMPK antagonist showed similar effects on the Sr-a1 knockout,significantly inhibiting the phagocytosis of NETs by BMDMs.In contrast,AMPK agonists enhanced this phagocytic process.In conclusion,medical ozone may alleviate the sepsis-induced lung injury through the AMPK/SR-A1 pathway,thereby enhancing the phagocytosis of NETs by macrophages.

AMPK activation by peri-sciatic nerve administration of ozone attenuates CCl-induced neuropathic pain in rats

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeu- tics. Ozone is widely used as an alternative therapy for many different pain conditions, with exact mechanisms still elusive. In this study, we found that a single peri-sciatic nerve injection of ozone decreased mechanical aUodynia and thermal hyperalgesia, and normalized the phosphorylation of protein kinase C y, N-methyI-D-aspartate receptor, and extracellular signal-regulated kinase in a chronic constriction injury （CCI） model in rat sciatic nerve. Meanwhile, ozone significantly suppressed CCI-induced activation of spinal microgUa. More importantly, the anti-nociceptive effect of ozone depended on the activation of 5＇-adenosine monophosphate （AMP）-activated protein kinase （AMPK）, which was proved by the fact that the phosphorylated AMPK level increased during the ozone therapy and AMPK antagonist abolished the effect of ozone in vivo and in vitro. In addition, direct injection of AMPK agonist could replicate the anti-nociceptive effect of ozone in CCI rats. In conclusion, our observations indicate that peri-sciatic nerve injection of ozone activates AMPK to attenuate CCI-induced neuropathic pain.

Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance

The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.